3D-QSAR Assisted Design of Novel 7-Deazapurine Derivatives as TNNI3K Kinase Inhibitors Using Molecular Docking and Molecular Dynamics Simulation

2020 ◽  
Vol 17 (2) ◽  
pp. 155-168
Author(s):  
Pavithra K. Balasubramanian ◽  
Anand Balupuri ◽  
Swapnil P. Bhujbal ◽  
Seung Joo Cho
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
3D Qsar ◽  
Structure Activity Relationship ◽  
Dynamics Simulation ◽  
Activity Relationship ◽  
Dual Function ◽  
Contour Maps ◽  
Structure Activity

Background: Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase that belongs to MAPKKK family. It is a dual-function kinase with tyrosine and serine/threonine kinase activity. Over-expression of TNNI3K results in various cardiovascular diseases such as cardiomyopathy, ischemia/reperfusion injury, heart failure, etc. Since, it is a cardiac-specific kinase and expressed only in heart tissue, it is an ideal molecular target to treat cardiac diseases. The main objective of the work is to study and understand the structure-activity relationship of the reported deazapurine derivatives and to use the 3D-QSAR and docking results to design potent and novel TNNI3K inhibitors of this series. Methods: In the present study, we have used molecular docking 3D QSAR, and molecular dynamics simulation to understand the structure-activity correlation of reported TNNI3K inhibitors and to design novel compounds of deazapurine derivatives with increased activity. Results: Both CoMFA (q2=0.669, NOC=5, r2=0.944) and CoMSIA (q2=0.783, NOC=5, r2=0.965) have resulted in satisfactory models. The models were validated using external test set, Leave-out- Five, bootstrapping, progressive scrambling, and rm2 metrics calculations. The validation procedures showed the developed models were robust and reliable. The docking results and the contour maps analysis helped in the better understanding of the structure-activity relationship. Conclusion: This is the first report on 3D-QSAR modeling studies of TNNI3K inhibitors. Both docking and MD results were consistent and showed good correlation with the previous experimental data. Based on the information obtained from contour maps, 31 novel TNNI3K inhibitors were designed. These designed compounds showed higher activity than the existing dataset compounds.

scholarly journals Discovery of New Hydroxyethylamine Analogs Against 3CLpro Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation and Structure-Activity Relationship Studies

2020 ◽  
Author(s):  
Sumit Kumar ◽  
Prem Prakash Sharma ◽  
Uma Shankar ◽  
Dhruv Kumar ◽  
Sanjeev K Joshi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Cysteine Protease ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Dynamics Simulation ◽  
Activity Relationship ◽  
Docking Score ◽  
Structure Activity ◽  
Novel Coronavirus

<p><br></p> <p>A novel coronavirus, SARS-CoV-2 has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of vaccine and potential therapeutics are critically essential. The crystal structure for main protease (M<sup>pro</sup>) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) was recently made available and is considerably similar to previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) enzyme was accomplished and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound <b>16</b> with docking score of -8.955 adhered to drug like parameters, and the Structure-Activity Relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of <b>16</b> within the binding pocket. Largly, our results supported that this novel compound <b>16</b> binds to the domain I & II, and domain II-III linker of 3CL<sup>pro</sup> protein, suggesting its suitablity as strong candidate for therapeutic discovery against COVID-19. Lead compound <b>16</b> could pave incredible directions for the design of novel 3CL<sup>pro</sup> inhibitors and ultimately therapeutics against COVID-19 disease.</p> <p><br></p> <p> </p>

scholarly journals Investigating the Binding Mode of Reversible LSD1 Inhibitors Derived from Stilbene Derivatives by 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulation

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4479
Author(s):  
Yongtao Xu ◽  
Zihao He ◽  
Min Yang ◽  
Yunlong Gao ◽  
Linfeng Jin ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Binding Free Energy ◽  
Clinical Stage ◽  
3D Qsar ◽  
Structure Activity Relationship ◽  
Field Analysis ◽  
Dynamics Simulation ◽  
Activity Relationship ◽  
Structure Activity ◽  
Stilbene Derivatives

Overexpression of lysine specific demethylase 1 (LSD1) has been found in many cancers. New anticancer drugs targeting LSD1 have been designed. The research on irreversible LSD1 inhibitors has entered the clinical stage, while the research on reversible LSD1 inhibitors has progressed slowly so far. In this study, 41 stilbene derivatives were studied as reversible inhibitors by three-dimensional quantitative structure–activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q 2 = 0.623, r 2 = 0.987, r pred 2 = 0.857) and comparative molecular similarity indices analysis (CoMSIA q 2 = 0.728, r 2 = 0.960, r pred 2 = 0.899) were used to establish the model, and the structure–activity relationship of the compounds was explained by the contour maps. The binding site was predicted by two different kinds of software, and the binding modes of the compounds were further explored. A series of key amino acids Val288, Ser289, Gly314, Thr624, Lys661 were found to play a key role in the activity of the compounds. Molecular dynamics (MD) simulations were carried out for compounds 04, 17, 21, and 35, which had different activities. The reasons for the activity differences were explained by the interaction between compounds and LSD1. The binding free energy was calculated by molecular mechanics generalized Born surface area (MM/GBSA). We hope that this research will provide valuable information for the design of new reversible LSD1 inhibitors in the future.

scholarly journals Discovery of New Hydroxyethylamine Analogs Against 3CLpro Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation and Structure-Activity Relationship Studies

2020 ◽  
Author(s):  
Sumit Kumar ◽  
Prem Prakash Sharma ◽  
Uma Shankar ◽  
Dhruv Kumar ◽  
Sanjeev K Joshi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Cysteine Protease ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Dynamics Simulation ◽  
Activity Relationship ◽  
Docking Score ◽  
Structure Activity ◽  
Novel Coronavirus

<p><br></p> <p>A novel coronavirus, SARS-CoV-2 has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of vaccine and potential therapeutics are critically essential. The crystal structure for main protease (M<sup>pro</sup>) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) was recently made available and is considerably similar to previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) enzyme was accomplished and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound <b>16</b> with docking score of -8.955 adhered to drug like parameters, and the Structure-Activity Relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of <b>16</b> within the binding pocket. Largly, our results supported that this novel compound <b>16</b> binds to the domain I & II, and domain II-III linker of 3CL<sup>pro</sup> protein, suggesting its suitablity as strong candidate for therapeutic discovery against COVID-19. Lead compound <b>16</b> could pave incredible directions for the design of novel 3CL<sup>pro</sup> inhibitors and ultimately therapeutics against COVID-19 disease.</p> <p><br></p> <p> </p>

scholarly journals Designing of the N-ethyl-4-(pyridin-4-yl)benzamide based potent ROCK1 inhibitors using docking, molecular dynamics, and 3D-QSAR

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11951
Author(s):  
Suparna Ghosh ◽  
Seketoulie Keretsu ◽  
Seung Joo Cho
Keyword(s):  
Molecular Dynamics ◽  
Heart Diseases ◽  
3D Qsar ◽  
Structure Activity Relationship ◽  
Field Analysis ◽  
Activity Relationship ◽  
Dimensional Structure ◽  
Valuable Insight ◽  
Contour Maps ◽  
Structure Activity

Rho-associated kinase-1 (ROCK1) has been recognized for its pivotal role in heart diseases, different types of malignancy, and many neurological disorders. Hyperactivity of ROCK phosphorylates the protein kinase-C (PKC), which ultimately induces smooth muscle cell contraction in the vascular system. Inhibition of ROCK1 has been shown to be a promising therapy for patients with cardiovascular disease. In this study, we have conducted molecular modeling techniques such as docking, molecular dynamics (MD), and 3-Dimensional structure-activity relationship (3D-QSAR) on a series of N-ethyl-4-(pyridin-4-yl)benzamide-based compounds. Docking and MD showed critical interactions and binding affinities between ROCK1 and its inhibitors. To establish the structure-activity relationship (SAR) of the compounds, 3D-QSAR techniques such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were used. The CoMFA (q2 = 0.774, r2 = 0.965, ONC = 6, and ${r}_{pred}^{2}$ = 0.703) and CoMSIA (q2 = 0.676, r2 = 0.949, ONC = 6, and ${r}_{pred}^{2}$ = 0.548) both models have shown reasonable external predictive activity, and contour maps revealed favorable and unfavorable substitutions for chemical group modifications. Based on the contour maps, we have designed forty new compounds, among which, seven compounds exhibited higher predictive activity (pIC50). Further, we conducted the MD study, ADME/Tox, and SA score prediction using the seven newly designed compounds. The combination of docking, MD, and 3D-QSAR studies helps to understand the coherence modification of existing molecules. Our study may provide valuable insight into the development of more potent ROCK1 inhibitors.

scholarly journals Simulation studies, 3D QSAR and molecular docking on a point mutation of protein kinase B with flavonoids targeting ovarian Cancer

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Suchitra Maheswari Ajjarapu ◽  
Apoorv Tiwari ◽  
Gohar Taj ◽  
Dev Bukhsh Singh ◽  
Sakshi Singh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Protein Kinase ◽  
Point Mutation ◽  
Protein Kinase B ◽  
3D Qsar ◽  
Dynamics Simulation ◽  
Simulation Studies

Abstract Background Ovarian cancer is the world’s dreaded disease and its prevalence is expanding globally. The study of integrated molecular networks is crucial for the basic mechanism of cancer cells and their progression. During the present investigation, we have examined different flavonoids that target protein kinases B (AKT1) protein which exerts their anticancer efficiency intriguing the role in cross-talk cell signalling, by metabolic processes through in-silico approaches. Method Molecular dynamics simulation (MDS) was performed to analyze and evaluate the stability of the complexes under physiological conditions and the results were congruent with molecular docking. This investigation revealed the effect of a point mutation (W80R), considered based on their frequency of occurrence, with AKT1 protein. Results The ligand with high docking scores and favourable behaviour on dynamic simulations are proposed as potential W80R inhibitors. A virtual screening analysis was performed with 12,000 flavonoids satisfying Lipinski’s rule of five according to which drug-likeness is predicted based on its pharmacological and biological properties to be active and taken orally. The pharmacokinetic ADME (adsorption, digestion, metabolism, and excretion) studies featured drug-likeness. Subsequently, a statistically significant 3D-QSAR model of high correlation coefficient (R2) with 0.822 and cross-validation coefficient (Q2) with 0.6132 at 4 component PLS (partial least square) were used to verify the accuracy of the models. Taxifolin holds good interactions with the binding domain of W80R, highest Glide score of − 9.63 kcal/mol with OH of GLU234 and H bond ASP274 and LEU156 amino acid residues and one pi-cation interaction and one hydrophobic bond with LYS276. Conclusion Natural compounds have always been a richest source of active compounds with a wide variety of structures, therefore, these compounds showed a special inspiration for medical chemists. The present study has aimed molecular docking and molecular dynamics simulation studies on taxifolin targeting W80R mutant protein of protein kinase B/serine- threonine kinase/AKT1 (EC:2.7.11.1) protein of ovarian cancer for designing therapeutic intervention. The expected result supported the molecular cause in a mutant form which resulted in a gain of ovarian cancer. Here we discussed validations computationally and yet experimental evaluation or in vivo studies are endorsed for further study. Several of these compounds should become the next marvels for early detection of ovarian cancer.

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